CGRP receptor ( Ki = 0.027 nM )

Rimegepant (BMS-927711, BHV-3000) is a potent, competitive, and selective antagonist of the human calcitonin gene-related peptide (CGRP) receptor with ki of 0.027 nM.

In vivo efficacy [1]
A novel noninvasive marmoset recovery model for in vivo efficacy assessment of CGRP receptor antagonists was developed in our laboratories, which utilizes laser Doppler facial blood flow as a surrogate for intracranial artery diameter. Briefly, marmosets were anesthetized and facial blood flow was increased by four intravenous (IV) administrations of hαCGRP (10 μg/kg) delivered at 45 min intervals (−30, 15, 60, and 105 min). The effect of antagonist, delivered subcutaneously (SC) at 0 min, on the hαCGRP-induced changes in facial blood flow was measured by laser Doppler flowmetry. In this model, compound 8 (Rimegepant, also known as BMS-927711) inhibited hαCGRP-induced increases in marmoset facial blood flow upon subcutaneous (SC) dosing. Compared to predose hCGRP control (−30 min), strong (>50%) inhibition of CGRP-induced effects on facial blood flow were observed with compound 8 dosed sc at 7 mg/kg at 15, 60, and 105 min postdose (Figure 2). Comparing activity versus exposure 15 min postdose, plasma levels of approximately 400 nM were associated with strong in vivo efficacy (>65% inhibition). In comparison, plasma levels of 5 above 1000 nM were needed for similar efficacy in this model. Peak inhibition for 8 was very strong at 75–80% at 60 and 105 min postdose, with corresponding plasma levels just below 800 nM (Figure 3).

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In vivo PK [1]
Compound 8 exhibited good oral bioavailability in the rat (FPO = 45%) and cynomolgus monkey (FPO = 67% as a solution). When dosed as a free base suspension of crystalline material, the oral bioavailability of 8 in the monkey remained good at 48%.

Competition for [125I]CGRP Binding Assay: [1]
The ability of 8 to inhibit the binding of radiolabeled human alpha CGRP ([125I]CGRP) to human CGRP receptors was measured using a radioligand competition assay. Human neuroblastoma SK-N-MC cells, endogenously expressing the CGRP receptor, were used as the CGRP receptor source (Aiyar et al., 2001). 8 was first solubilized and serially diluted in 100% DMSO. Compound was further diluted 25 fold into assay buffer (50 mM Tris-Cl pH 7.5, 5 mM MgCl2, 0.005% Triton X-100) and transferred (50 µl) into 96 well assay plates. [125I]CGRP was diluted to 72 pM in assay buffer and 50 µl was added to each well (final concentration 18 pM in assay – Kd=27.7 pM). SK-N-MC membrane pellets were thawed, diluted in assay buffer with fresh 0.1% mammalian protease inhibitor cocktail, and homogenized. Homogenate (5 to 10 µg protein) was then added in a volume of 100 µl to each well. The assay plates were incubated at room temperature (25 °C) for two hours. Assays were terminated by the addition of excess cold wash buffer (50 mM Tris-Cl pH 7.5, 0.1% BSA) immediately followed by filtration over glass fiber filters pre-soaked in 0.5% PEI. Non-specific binding was defined as binding in the presence of 1 µM β-CGRP. Protein bound radioactivity was measured using a gamma scintillation counter. The IC50 was defined as the concentration of compound required to inhibit 50% of radioligand binding.

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CGRP receptor binding in other species [1]
S6 8 was tested for its potency at the CGRP receptor for marmoset (common marmosets (Callithrix jacchus)). Radioligand binding assays were used to assess the activity: 50 µg of brain homogenates from each species were used as the receptor source and 15 pM [125I]CGRP as the radioligand.

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CYP Inhibition Using Human Recombinant Enzymes[1]
The capacity of the test compounds to inhibit cDNA-derived CYP enzymes in microsomes prepared from baculovirus-infected insect cells was measured using either 3-cyano-7-ethoxycoumarin (CYP1A2 and CYP2C19), 7-methoxy-4-trifluoromethylcoumarin (CYP2C9) or 3-[2-(N,N-diethyl-Nmethylamino)ethyl]-7-methoxy-4-methylcoumarin (CYP2D6) as model substrates. CYP3A4 was tested with two substrates, 7-benzyloxy-4-trifluoromethylcoumarin (BFC) and benzoylresorufin. The 50% inhibitory concentration (IC50) for the test compound was determined for each enzyme. A single concentration of each model substrate, at approximately the apparent Km with the exception of BFC which was tested below the apparent Km, was incubated with 10 concentrations of the compound of interest ranging from 2 nM to 40 µM in 0.2% v/v DMSO. Metabolism of the model substrate was assayed by the production of 7-hydroxy-3-cyanocoumarin, 3-[2-(N,N-diethylamino)ethyl]-7-hydroxy-4- methylcoumarin, 7-hydroxy-4-trifluoromethylcoumarin or resorufin metabolites, and measured via fluorescence detection. Assays were conducted in 384-well microplates in a total volume of 30 µl. Incubations were performed for 45 min (20 min for the CYP3A4 BFC assay) with microsomes prepared from baculovirus-infected insect cells containing cDNAderived CYP enzymes, and utilized an NADPH generating system.

SK-N-MC CGRP Cellular/Functional Assay [1]
The CGRP receptor complex is coupled to the Gαs class of G protein. Binding of CGRP to this complex leads to the production of cyclic AMP (adenosine 3'5'-cyclic monophosphate) via Gαs-dependent activation of adenylate cyclase. 8 was evaluated as an inhibitor of human CGRP receptor signaling by measuring the compounds ability to inhibit CGRP-stimulated cyclic AMP formation in attached SK-N- S5 MC cells. SK-N-MC cells were preincubated with various concentrations of 8 or vehicle for 15 minutes. Agonist (300 pM αCGRP, EC50 = 26.7 + 2.7 pM n=3) was added and the samples were incubated at room temperature for 30 minutes. The cells were lysed and evaluated using an HTRF based cAMP detection kit. IC50 values were defined as the concentration of compound required to inhibit 50% of the 300 pM CGRP-stimulated cAMP production.

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Permeability and P-glycoprotein Interaction [1]
Permeability of 8 was assessed by the non-cell-based parallel artificial membrane permeability assay (PAMPA), as well as the cell-based Caco-2 cell model. The PAMPA permeability study was conducted with 100 µM 8 at room temperature for 4 hours at pH 5.5 and 7.4 using pION© lipid solution. The studies were performed in triplicate (i.e., 3 wells per compound) with mean values reported in nm/second. Caco-2 cell studies were performed with the monolayers cultured for approximately 21 days. Bi-directional permeability studies for 8 were conducted at concentrations of 3.7 to 100 µM, pH 7.4. A follow-up bi-directional study was also performed for 8 (3 µM, pH 7.4) in presence of a P-gp inhibitor (ketoconazole 20 µM and cyclosporin 20 µM on both sides). The inhibition of the transport of [ 3H]-digoxin (initial concentration 5 µM), a P-gp substrate, across the Caco-2 cell membrane by 8 (initial concentration 10 µM) was studied to evaluate the potential inhibitory effect of the compound on P-gp.

In Vivo Efficacy of 8 [Rimegepant (BMS927711)] in Marmoset Facial Blood Flow[1]
To assess in vivo efficacy and duration of action, a control increase in facial blood flow is induced by administration of hαCGRP (10 µg/kg, IV) 30 min prior (-0.5 hr) to drug delivery. The CGRP antagonist compound under study is administered at time zero (0 min) and three additional hαCGRP challenges are delivered at 45 min intervals for ~2 hr (data collected at 0.25, 1 and 1.75 hrs post-dose). Plasma samples are obtained just before each of the three post-dose hαCGRP administrations, to define the antagonist levels on board at the time of hαCGRP agonist challenge. Each antagonist is administered across a range of doses to define the no-effect, first significant effect and maximal peak effect dose. In the present study, 8 [Rimegepant (BMS927711)] is dosed from 0.3 to 7 mg/kg, SC. The highest dose (7 mg/kg for 8 [Rimegepant (BMS927711)]) represents the maximum dose deliverable within solubility limits and constrained by vehicle volumes that do not disrupt baseline facial blood flow. Following testing, animals are returned to the transport cage and placed on a temperature controlled surface that keeps the animals warm until fully awake and ambulatory. Animals may be tested again after a 14-21 day rest and washout period.

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In Vivo Methods – Pharmacokinetics in Rat and Cynomolgus Monkey [1]
In the rat and monkey studies described below, 8 [Rimegepant (BMS927711)] was administered IV as a solution in a polyethylene glycol 400 (PEG-400)/ethanol (90:10, v/v). Rat Male Sprague-Dawley rats (250-350 g) were used in the PK studies of 8 [Rimegepant (BMS927711)]. Blood samples (~0.3 mL) were collected from the jugular vein into K3EDTA-containing tubes and then centrifuged at 4°C (1500-2000 x g) to obtain plasma, which was stored at -20°C until analysis by LC/MS/MS. In an oral bioavailability study with 8 [Rimegepant (BMS927711)], 2 groups of animals (N = 3 per group) received the compound as an intra-venous (IV) bolus (1 mg/kg) via a jugular vein cannula or as a solution by oral gavage (10 mg/kg to fasted rats). The oral solution contained 8 [Rimegepant (BMS927711)] dissolved in PEG-400/water (90:10, v/v). Serial blood samples were obtained predose and at 0.03 and 0.17 (IV only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 S9 hours post dose. Plasma samples, obtained by centrifugation at 4°C (1500-2000 x g), were stored at -20°C until analysis.

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Cynomolgus Monkey [1]
The PK of 8 was evaluated in a crossover-design study in male cynomolgus monkeys. Following an overnight fast (oral only), 3 animals (5.4 to 6.3 kg) received 8 [Rimegepant (BMS927711)] by IV infusion (1 mg/kg over 5 minutes) via a femoral vein and by oral gavage as either a solution (10 mg/kg dissolved in 79.8% PEG400; 20% N-methylpyrrolidone; 0.2% Tween 80) or suspension of crystalline free base (10 mg/kg suspended in 98.95% water;1% povidone K-30; 0.05% docusate sodium), with at least a 2- week washout between treatments. Serial blood samples (~0.3 mL) were collected from a femoral artery predose and at 0.083, 0.17 (IV only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 hours post dose, and centrifuged at 4°C (1500-2000 x g) to obtain plasma. Samples were stored at -20°C until analysis by LC/MS/MS.

Absorption, Distribution and Excretion
The absolute oral bioavailability of rimegepant is approximately 64%. Following oral administration of the orally disintegrating tablet, maximum plasma concentrations were achieved at 1.5 hours (Tmax). When administered with a high-fat meal, Tmax is delayed by 1 hour, Cmax is decreased by 42-53%, and AUC is decreased by 32-38%. The clinical significance of this difference in pharmacokinetics is unknown.
Following oral administration of radiolabeled rimegepant in healthy subjects, 78% of the administered radioactivity was recovered in feces and 24% in urine. Unchanged parent drug was the major component in each, comprising 42% and 51% of the recovered doses, respectively.
At steady state, the volume of distribution is approximately 120 L.

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Metabolism / Metabolites
Rimegepant is metabolized by CYP3A4 and, to a lesser extent, CYP2C9. Specific metabolites of rimegepant have not been characterized and no major metabolites have been detected in plasma. Approximately 77% of an administered dose is eliminated unchanged, suggesting metabolism is likely to be a minor means of drug elimination.

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Biological Half-Life
The elimination half-life in healthy subjects is approximately 11 hours.

Hepatotoxicity
In preregistration controlled trials of rimegepant in several thousand patients, mild-to-moderate serum aminotransferase elevations arose in a small percentage of patients (1% to 2%) and overall rates were not different from those in placebo recipients. In the controlled trials and subsequently with general use, there have been no reports of clinically apparent liver injury attributed to ubrogepant. In contrast, telcagepant, the initial oral CGRP receptor antagonist evaluated as therapy for migraine headaches, was abandoned during development because of several instances of clinically apparent liver injury in recipients that was characterized by marked elevations in serum aminotransferase levels and symptoms of fatigue, nausea and abdominal discomfort arising within 2 to 4 weeks of starting therapy which rapidly resolved with stopping therapy. Similar episodes have not been reported with rimegepant.
Likelihood score: E (unlikely cause of clinically apparent acute liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of rimegepant during breastfeeding. However, amounts in breastmilk are low and would not be expected to cause any adverse effects in breastfed infants. If rimegepant is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Rimegepant is approximately 96% plasma protein-bound. The specific proteins to which rimegepant binds have not been elucidated.

[1]. J Med Chem . 2012 Dec 13;55(23):10644-51.

Rimegepant is an oral antagonist of the CGRP receptor developed by Biohaven Pharmaceuticals. It received FDA approval on February 27, 2020 for the acute treatment migraine headache, and was subsequently approved by the European Commission in April 2022 for both the treatment and prevention of migraines. While several parenteral antagonists of CGRP and its receptor have been approved for migraine therapy (e.g. [erenumab], [fremanezumab], [galcanezumab]), rimegepant and [ubrogepant] were the only CGRP antagonists that possessed oral bioavailability until the approval of [atogepant] in 2021. The current standard of migraine therapy involves abortive treatment with "triptans", such as [sumatriptan], but these medications are contraindicated in patients with pre-existing cerebrovascular and cardiovascular disease due to their vasoconstrictive properties. Antagonism of the CGRP pathway has become an attractive target for migraine therapy as, unlike the triptans, oral CGRP antagonists have no observed vasoconstrictive properties and are therefore safer for use in patients with contraindications to standard therapy.
Rimegepant is a Calcitonin Gene-related Peptide Receptor Antagonist. The mechanism of action of rimegepant is as a Calcitonin Gene-related Peptide Receptor Antagonist.
Rimegepant is a small molecule inhibitor of the calcitonin gene-related peptide (CGRP) receptor that blocks the action of CGRP, a potent vasodilator believed to play a role in migraine headaches. Rimegepant is approved for treatment of acute migraine attacks. In clinical trials, rimegepant was generally well tolerated with only rare instances of transient serum aminotransferase elevations during therapy and with no reported instances of clinically apparent liver injury.
See also: Rimegepant Sulfate (active moiety of).

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Drug Indication
Rimegepant is indicated for the acute treatment of migraine with or without aura in adults. Rimegepant is also indicated for the prevention of episodic migraine in adults.
Vydura is indicated for theAcute treatment of migraine with or without aura in adults; Preventative treatment of episodic migraine in adults who have at least 4 migraine attacks per month.
Treatment of migraine headaches
Prevention of migraine headaches

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Mechanism of Action
The currently accepted theory of migraine pathophysiology considers dysfunction of the central nervous system, in particular the trigeminal ganglion, to be the root cause behind the condition. Activation of the trigeminal ganglion triggers the stimulation of trigeminal afferents that project to the spinal cord and synapse on various pain-sensing intra- and extracranial structures, such as the dura mater. Pain signals are then further transmitted via second-order ascending neurons to the brainstem, hypothalamus, and thalamic nuclei, and from there to several cortical regions (e.g. auditory, visual, motor cortices). The trigeminal ganglion appears to amplify and perpetuate the migraine headache pain through the activation of perivascular fibers and the release of molecules involved in pain generation, such as calcitonin gene-related peptide (CGRP). The α-isoform of CGRP, expressed in primary sensory neurons, is a potent vasodilator and has been implicated in migraine pathogenesis - CGRP levels are acutely elevated during migraine attacks, return to normal following treatment with triptan medications, and intravenous infusions of CGRP have been shown to trigger migraine-like headaches in migraine patients. In addition to its vasodilatory properties, CGRP appears to be a pronociceptive factor that modulates neuronal excitability to facilitate pain responses. Rimegepant is an antagonist of the calcitonin gene-related peptide receptor - it competes with CGRP for occupancy at these receptors, preventing the actions of CGRP and its ability to amplify and perpetuate migraine headache pain, ultimately terminating the headache.

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Pharmacodynamics
Rimegepant helps to abort migraine headaches by preventing the activity of a pronociceptive molecule that has been implicated in migraine pathophysiology. It is intended for use as an abortive migraine therapy and therefore has a relatively rapid onset of effect, with most efficacy trials evaluating for effect at the 2 hour mark. Rimegepant does not require dose adjustment in patients with mild, moderate, or severe renal impairment, nor does it require dose adjustment in patients with mild or moderate hepatic impairment. In clinical trials, plasma concentrations of rimegepant were significantly higher in patients with severe (i.e. Child-Pugh C) hepatic impairment - it should therefore be avoided in this population. Hypersensitivity reactions have occurred during clinical studies and patients should be made aware of this possibility. Rimegepant should be discontinued immediately if hypersensitivity reaction occurs.

C28H28F2N6O3

534.57

534.219

C, 62.91; H, 5.28; F, 7.11; N, 15.72; O, 8.98

1289023-67-1

1289023-67-1; 1642783-82-1 (0.5 sulfate); 1374024-48-2 (0.5 sulfate 1.5 hydrate); 2377164-85-5 (0.5 sulfate 3 hydrate)

51049968

Solid powder

1.5±0.1 g/cm3

1.676

1.73

2

8

4

39

891

3

N[C@H]1[C@H](C2=C(F)C(F)=CC=C2)CC[C@@H](OC(N3CCC(N4C(C=CC=N5)=C5NC4=O)CC3)=O)C6=NC=CC=C61

KRNAOFGYEFKHPB-ANJVHQHFSA-N

InChI=1S/C28H28F2N6O3/c29-20-6-1-4-17(23(20)30)18-8-9-22(25-19(24(18)31)5-2-12-32-25)39-28(38)35-14-10-16(11-15-35)36-21-7-3-13-33-26(21)34-27(36)37/h1-7,12-13,16,18,22,24H,8-11,14-15,31H2,(H,33,34,37)/t18-,22+,24-/m0/s1

[(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl] 4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

5%DMSO + Corn oil: 5.0mg/ml (9.35mM) (Please use freshly prepared in vivo formulations for optimal results.)